Atrial fibrillation is the most common arrhythmia seen in clinical practice and has a substantial impact on the healthcare delivery system.  The risk of thromboembolic stroke, perhaps the most feared complication of atrial fibrillation, is 3-5 times higher in patients with atrial fibrillation (non-valvular) than the general population.  Until the recent emergence of direct thrombin inhibitors and factor Xa inhibitors, antithrombotic therapy in atrial fibrillation was achieved with aspirin or warfarin, both of which proved to be cost-effective strategies when compared to no therapy.  Now, newer agents, such as the direct thrombin inhibitor dabigatran, are lowering thromboembolic events, reducing the risk of fatal and intracerebral hemorrhage, and eliminating the need for costly therapeutic level monitoring.  Multiple analyses have shown that the use of dabigatran, in particular, is a cost-effective approach to antithrombotic therapy in atrial fibrillation, at anywhere from $16,385 to $86,000 per quality-adjust life-year (QALY) gained.  It has been shown to be especially cost-effective (QALY < $50,000) for patients with a CHADS₂ score of > 3 (unless INR control was excellent) and for patients with a CHADS₂ of 2 and high risk of hemorrhage.  In addition, factor Xa inhibitors, such as rivaroxaban (recently approved by the FDA) and apixaban, may exhibit the same cost savings as dabigatran in terms of reduction of bleeding and elimination of therapeutic level monitoring costs.  Going forward, the use of these agents and their role in thromboembolic stroke prophylaxis will need to be evaluated on a patient-by-patient basis, taking into consideration the patient’s stroke risk, risk of bleeding, and quality of life post-therapy.